Close collaboration leads to vital understanding of Alzheimer

Molecular & Cellular Technologies
  • Thomas Hankemeier
  • Cock van Duijn

Many aspects of Alzheimer’s disease are still mysterious. But by connecting their respective fields of genetics and metabolomics, Cornelia van Duijn and Thomas Hankemeier have been able to enhance fundamental understanding of this disease. This approach is now starting to pay off, as they have identified metabolites that predict Alzheimer’s.

“Genes are the basis of life,” says Van Duijn, Professor of Genetic Epidemiology at Erasmus MC. “The genome contains the blueprints of the proteins that regulate physical processes necessary to grow into a human being, while at the same time, our proteins are turned into active substances that define what goes right and what goes wrong inside the body. Ultimately, the metabolism is the gate keeper of health and disease.”

This explains why Van Duijn and metabolomics specialist Professor Thomas Hankemeier were instantly interested in collaborating when they met at a meeting of the steering committee of the Centre of Medical Systems Biology of the Netherlands Genomics Institute (NGI). Both are interested in finding  out what goes wrong on the molecular level in the case of disease. “What does an error in the genome mean?” asks Van Duijn. “A failing gene does not make you sick per se, but the metabolites that result from this failure do. This is what tightly interconnects our fields of interest.”

Predictors for Alzheimer’s

Alzheimer’s disease is characterised by a lengthy period of developing pathology, both before and after diagnosis. “Thanks to the prospective, population-based Rotterdam and the Erasmus Rucphen Study, we now have the detailed data we need to find out how metabolites affect the progression of this disease,” says Van Duijn. “We’ve been following one cohort for more than25 years. So we know the genetics of the participants, we know who developed the disease, and by using stored samples we can trace back in time what minute changes took place in the blood of the individuals involved. For a disease such as diabetes, it has been obvious for a long time that metabolites can be found in the blood. For Alzheimer’s, however, this has been less obvious. But we did find evidence – that can be replicated – that certain metabolites in the blood determine cognitive functioning early in life and are connected to later development of Alzheimer’s. We’ll be presenting this evidence in forthcoming publications.”

Finding these metabolites will lead the way to predicting - and preventing - Alzheimer’s. Cardiovascular diseases, high cholesterol level, high blood pressure and little physical exercise are established risk factors. Through our metabolomics research, we aim to find novel ones. Prof.dr. Cock van Duijn Erasmus MC & Leiden University

Key to drugs

“Characterising metabolites in patients’ blood samples sheds light on novel aspects of diseases,” says Van Duijn, “but it doesn’t always tell the full story. Yes, people with Alzheimer’s may have metabolites in their blood that stand out in comparison to healthy people’s blood. But you need to find out what’s happening in the brain in order to take that extra step of translating the science into potential therapies. And because invasive research on the living brain is impossible, you have to model what happens in the brain.”

This can be done with Induced Pluripotent Stem cells (IPS). Blood and skin cells from the patients are “programmed back” to induce stem cells that can be transferred into various relevant types of brain cells, such as neurons, astrocytes and gliacells. These can be joined with a blood vessel, including the endothelium, to build an organ-on-a-chip. “As it happens, Hankemeier also held the key to that via organ-on-a-chip company Mimetas in Leiden,” says Van Duijn. “In the brain-model-on-a-chip, we can study the behaviour of the various brain cells and characterise what metabolites are formed. The model even includes the blood/brain barrier and will provide insight into how metabolites pass the blood/brain barrier to eventually end up in the blood.”

“That’s the exciting phase we’ve now entered,” Van Duijn concludes. “We have a model for translational research that won us substantial funding from the European Horizon 2020 Programme CoSTREAM and the Innovative Medicines Initiative, as well as from industry. This enables us to establish under which conditions ‘wrong’ metabolites are formed or not, and how they get from the blood into the brain. Once we understand the process, the flaws in it and the substances that are formed, we’ll have the key to study possible drugs that we can test in the same model. We’re not entirely there yet, but that’s where we’re heading.” 

Collaboration essential

Hankemeier and Van Duijn, together with their colleagues Dorret Boomsma (VUmc) and Eline Slagboom (LUMC), have now arrived at the point where the first results for various diseases are becoming available as part of the BBMRI-NL program. “We see consistent results throughout the epidemiology, the genetics and the biobank involved. We never doubted that it would work once the sample size was large enough, but now we’ve reached the point where we’re ready to publish our results so far. I’m certainly very glad with what we’ve achieved this year.”

What has contributed to the success so far? “In general, multidisciplinary collaboration is important,” says Van Duijn. “But that in itself is not very revealing. We discovered that you need to collaborate really intensively and in a targeted manner to get to know the essence of each other’s fields to take things further. Thomas Hankemeier and I therefore decided to work one day per week at each other’s location. It was an essential step for our project.”

Interview by: Leendert van der Ent